DESCRIPTION: The long-term goal of this proposal is to identify genes that are directly responsible for lung tumor resistance to chemical carcinogens. The specific aims are: 1) Fine mapping of QTLs from a 20-30 cM region to a 1-2 cM subregion of the chromosome, which will be accomplished by the following two complementary approaches. The first is to develop a series of congenic mice through repeated backcrossing with the parental strain carrying the resistance allele. The resulting congenic strain of mice will then be used to generate congenic mapping analysis of the chromosomal regions associated with the QTLs. The second is to conduct deletion mapping analysis of the chromosomal regions associated with the QTLs in mouse lung tumors derived from F1 hybrid mice, and to define a minimal region of chromosomal loss for each QTL. 2) Positional cloning of selected QTLs. A contig containing overlapping BAC/P1 clones for each fine mapped QTL (1-2 cM) will be constructed using closely linked polymorphic markers and genes. Candidate genes will be isolated by direct screening of cDNA libraries with the BAC/P1 clones. Candidate genes will be analyzed for sequence variations in the coding region and differences in RNA expression between parental alleles. 3) Functional characterizations will be conducted under this proposal to either confirm or eliminate candidate genes for mouse lung tumor resistance QTLs.